The discovery of nitric oxide (NO) demonstrated that cells could communicate via the manufacture and local diffusion of an unstable lipid soluble molecule. Since the original demonstration of the vascular relaxant properties of endothelium derived NO, this fascinating molecule has been shown to have multiple, complex roles within many biological systems. This review cannot hope to cover all of the recent advances in NO biology, but seeks to place the discovery of NO in its historical context, and show how far our understanding has come in the past 20 years. The role of NO in mitochondrial respiration, and consequently in oxidative stress, is described in detail because these processes probably underline the importance of NO in the development of disease.